March 7, 2017 by Jill Anderson, in CBD (Cannabidiol)

Early findings in clinical studies have shown CBD to have a wide range of effects that may be therapeutically useful, including anti-seizure, antioxidant, neuroprotective, anti-inflammatory, analgesic, anti-tumor, anti-psychotic, and anti-anxiety properties.

For a growing number of people, CBD is now seen as a miracle cure – a sort of game-changing, non-psychoactive, non-addictive, wonder drug that has been missing from modern medicine.

How does it work? CBD’s mechanism of action as an inhibitor

Cellular stress and inflammation are some of the areas in which CBD is particularly helpful.

When cells are damaged through injury or stress, a purine nucleoside called adenosine is released in the body which primarily helps to prevent tissue damage during instances of hypoxia, ischemia, and seizure activity. Then in a process called adenosine signaling, the adenosine receptor A2A is activated which produces an anti-inflammatory response.

The problem is that the effects of adenosine are short lived.

Not long after its release there is adenosine uptake, where the nucleoside is rapidly taken up into adjacent cells by protein transporters called equilibrative nucleoside transporters (ENTs) and then metabolized.

Now here’s the good news. CBD acts to inhibit adenosine uptake by acting as a competitive inhibitor. By competing with adenosine to bind with ENT, this increases the availability of adenosine in the extracellular space which allows it to continue producing its anti-inflammatory response.

The implications of this discovery are huge.

For example, CBD’s inhibitor qualities could help as supplementary therapy for cancer patients by increasing the effectiveness of antifolate drugs. And because it enhances adenosine signaling, CBD also shows promise for treating inflammation, seizures, and reducing the amount of damage done to live tissue following heart or brain ischemia.

Through ENT inhibition, CBD has also been show to enhance THC’s effects by counteracting some of the consequences of CB1 activation. This means that users are less likely to develop psychotic symptoms when their cannabis preparation has a high CBD to THC ratio. Also along those lines, cannabidiol has been shown to allow patients to tolerate higher amounts of THC – a great benefit for people who suffer from multiple sclerosis. In fact, CBD may also supplement the anti-spastic effects of THC as well.

CBD inhibits the enzyme fatty acid amide hydroxylase (FAAH) which has been shown to help reduce inflammation-induced intestinal hypermotility in the intestine. And similar to how it works with adenosine, CBD inhibits the reuptake of anandamide to enhance anandamide signaling as well. This has been shown to alleviate psychotic symptoms of schizophrenia.

CBD also inhibits T-type Ca2+, 5-Lipoxygenase, and 15-Lipoxygenase, which could play a role in nociception, antiepileptic effects, tumor tissues, and atherosclerosis.

CBD, the antagonist

The G protein-coupled receptor 55 (GPR55) is another interesting receptor found throughout the body.

It is a recently discovered orphan G protein-coupled receptor that can be activated by a number of cannabinoid ligands. Because GPR55 has the ability to bind with cannabinoids (much like CB1 and CB2), researchers speculate that it could be a novel CB receptor.

Although CBD boasts the ability to bind to GPR55, it functions as an antagonist which does not activate the receptor and can block the activity of other agonists (or stimulants). One such example is in the role CBD can play in the gastrointestinal tract.

GPR55 exists throughout the whole intestine and when the intestine has decreased motility and becomes inflamed due to inflammatory bowel disease, GPR55 is activated and levels tend to spike.

However, in an experiment with mice, researchers demonstrated that CBD’s antagonist properties inhibited GPR55 activation in the gut. Their findings showed that CBD was associated with a reduction of pro-inflammatory cytokines, inhibition of neutrophil infiltration, and prevention of tissue damage.

Because GPR55 is found in many other parts of the body including the brain, more research is needed to better understand the relationship between CBD and GPR55.

But as an antagonist, CBD has been effective with other mechanisms of action as well. CBD is also an antagonist of TRPM8, known as the cold and menthol receptor 1 (CMR1), which may help explain its analgesic effects and can have a potential role in treating prostate cancer.

CBD, the agonist and other mechanisms of action

Aside from being an inhibitor and an antagonist, CBD also displays other mechanisms of action as well.

The opposite of an antagonist, an agonist is a substance that acts like another substance and therefore stimulates an action. In these cases, CBD binds to a receptor and activates it to produce a response. CBD is an agonist (or stimulant) of:

TRPA1. By binding with and activating TRPA1, it increases the amount of calcium ions (CA2+) in the TRPA1-HEK-293 cells which may play a potential role in CBD’s analgesic effects.

TRPV1. CBD also increases the amount of CA2+ in the TRPV1-HEK-293 cells which may contribute to CBD’s antipsychotic and analgesic effects.

TRPV2. CBD mobilizes Ca2+ in TRPV2-HEK-293 cells to activate TRPV2 which may mediate CGRP (Calcitonin gene-related peptide), a peptide that plays an integral role in migraines.

PPARγ. Peroxisome proliferator-activated receptor gamma, or PPARγ, regulates fatty acid storage and glucose metabolism. PPARγ activation by CBD has been shown to induce vasorelaxation. It may also help turn cells in connective tissues that produce collagen into fat cells that specialize in storing energy as fat. PPARγ stimulation may inhibit the growth of several cancers as well.

5-HT1A. Serotonin (5-hydroxytryptamin) is an important neurotransmitter that is active in constricting smooth muscles, regulating cyclic body processes, and transmitting impulses between nerve cells to mediate both excitatory and inhibitory neurotransmission. It is responsible for maintaining mood balance and contributing to well-being and happiness. The 5-HT1A receptor is a subtype of the serotonin receptor located in central and peripheral nervous systems. Activation of this receptor has been involved in the mechanism of action of anxiolytic, antidepressant and antipsychotic medications. 5-HT1A is also involved in CBD-induced antischemic and anxiolytic properties as well.

In another mechanism of action, CBD acts as a positive allosteric modulator of glycine receptors.

A positive allosteric modulator is a substance that indirectly amplifies the effects of an agonist at a target receptor. In the case of glycine receptors, CBD targets a1 and a3 glycine receptors and may play a role in chronic pain management after inflammation or nerve injury.

CBD has also been shown to regulate intracellular calcium ions which could mean CBD has neuroprotective and antiepileptic properties.

And finally, CBD is also a suppressor of tryptophan degradation.

Tryptophan is an essential amino acid that is necessary for the growth and proliferation of various cells as well as pathogens. It is also the precursor of the neurotransmitters serotonin and nicotinamide adenine dinucleotide (NAD).

But when patients suffer from chronic inflammatory disease, their tryptophan levels drop as they get degraded by the enzyme indoleamine-2,3-dioxygenase (IDO). This decreases the immunoresponsiveness of patients and ultimately influences their mood and physical strength, which can lead to fatigue, weight loss, and neuropsychiatric disorders. CBD acts as a suppressor of tryptophan degradation, which may play a potential role in pain, inflammation, and depression treatment.

These are just some of the ways in which CBD is helping people all over the country. Because it’s a natural, non-psychoactive, non-addictive, and highly therapeutic ingredient in cannabis, it has many advantages over THC and many harmful pharmaceutical drugs. As research continues to explore CBD’s medicinal qualities, we’re bound to see new scientific breakthroughs in the years ahead.

But there’s still a lot of work to be done.

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